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Updated: Feb 5, 2026
A Porcine Heterotopic Heart Transplantation Protocol for Delivery of Therapeutics to a Cardiac Allograft
Published on: February 14, 2022
Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection
Ingrid Gan1,2,3, Jifu Jiang1, Dameng Lian1
1Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, London, Canada.
Abstract:
Transplantation is invariably associated with programmed cell death including apoptosis and necrosis, resulting in delayed graft function and organ rejection. We have demonstrated the contribution of necroptosis to mouse microvascular endothelial cell (MVEC) death and transplant rejection. Organ injury results in the opening of mitochondrial permeability transition pores (mPTPs), which can trigger apoptotic molecules release that ultimately results in cell death. The effect of mPTPs in the necroptotic pathway remains controversial; importantly, their role in transplant rejection is not clear. In this study, tumor necrosis factor-α triggered MVECs to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, inhibition of mPTP opening could also inhibit necroptotic cell death. Cyclophilin-D (Cyp-D) is a key regulator of the mPTPs. Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis (n = 3, P < .00001). Additionally, inhibition of Cyp-D attenuated RIPK3-downstream mixed-lineage kinase domain-like protein phosphorylation. In vivo, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice posttransplant compared with wild-type grafts (n = 7, P < .0001). Our study results suggest that the mPTPs may be important mechanistic mediators of necroptosis in cardiac grafts. There is therapeutic potential in targeting cell death via inhibition of the mPTP-regulating molecule Cyp-D to prevent cardiac graft rejection.
Insights
Targeting mitochondrial permeability transition pores (mPTPs) via Cyclophilin-D (Cyp-D) inhibition can prevent necroptosis, a programmed cell death pathway. This approach shows therapeutic potential for reducing cardiac graft rejection in transplantation.
Area of Science:
- Immunology
- Cell Biology
- Transplantation Medicine
Background:
- Transplantation is frequently complicated by programmed cell death, including apoptosis and necrosis, leading to delayed graft function and rejection.
- Necroptosis, a specific form of programmed cell death, has been implicated in microvascular endothelial cell death and transplant rejection.
- Mitochondrial permeability transition pores (mPTPs) are involved in cell death pathways, but their role in necroptosis and transplant rejection is not fully understood.
Purpose of the Study:
- To investigate the role of mPTPs in necroptosis during transplant rejection.
- To determine if inhibiting mPTP opening can prevent necroptosis and improve graft survival.
- To explore the therapeutic potential of targeting Cyclophilin-D (Cyp-D), a key regulator of mPTPs, in preventing cardiac graft rejection.
Main Methods:
- Triggered necroptosis in mouse microvascular endothelial cells (MVECs) using tumor necrosis factor-α.
- Assessed the effect of mPTP inhibition and Cyclophilin-D (Cyp-D) deficiency/inhibition on MVEC necroptosis and RIPK3-dependent signaling.
- Evaluated cardiac allograft survival in vivo in wild-type and Cyp-D-deficient mice.
Main Results:
- Tumor necrosis factor-α-induced necroptosis in MVECs was dependent on RIPK1/3 and inhibited by blocking mPTP opening.
- Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis and attenuated RIPK3-downstream signaling.
- Cardiac grafts from Cyp-D-deficient mice exhibited significantly prolonged survival in allogeneic recipients compared to wild-type grafts.
Conclusions:
- Mitochondrial permeability transition pores (mPTPs) are crucial mediators of necroptosis in cardiac grafts.
- Inhibition of the mPTP-regulating molecule Cyp-D effectively prevents necroptosis in vitro and in vivo.
- Targeting Cyp-D offers a promising therapeutic strategy to prevent cardiac graft rejection.
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